Description: The overall goal of this proposal is to select from five lead compounds, a novel, highly potent acyclic nucleoside phosphonate antiviral for the treatment of drug resistant HIV infection. HIV drug resistance, both acquired and transmitted, is highly prevalent and represents a major challenge to effective therapeutic management. Three acyclic nucleoside phosphonates are approved for oral therapy of viral diseases;of these, tenofovir is marketed for HIV infection. Acyclic nucleoside phosphonates have several drawbacks. As a class, they are not absorbed orally, their penetration of the cellular membrane is highly restricted by their double negative charge and, once in the body, they are selectively taken up by an active transporter in kidney proximal tubules causing nephrotoxicity. Some of these problems can be overcome by esterifying the phosphonate oxygens. Tenofovir disoproxil improves oral absorption, but the disoproxils are removed and doubly negatively charged tenofovir circulates, exposing the kidney to potential nephrotoxicity and retaining the limitation of cell membrane penetration. To address these drawbacks, we have developed a novel approach which involves esterification of a single phosphonate oxygen with an alkoxyalkyl group. This increases oral absorption, cell penetration and enhances antiviral activity against HIV by 3 or more logs in vitro. To date, we have identified five novel, orally active highly potent alkoxyalkyl esters of acyclic nucleoside phosphonates which are active in the nanomolar or picomolar range against HIV-1 and have full or nearly full activity against a panel of drug resistant HIV variants. We propose detailed preclinical evaluation against an expanded panel of drug resistant HIV variants including TAMS, M184V, K65R, 69 insert, 151 complex and multidrug resistant HIV mutants and clinical isolates. The most promising candidate will be selected for detailed metabolic, pharmacokinetic, toxicologic evaluations with the goal of bringing the most promising new drug toward IND status for drug resistant HIV infection. Lay summary: Drug resistance develops in a high percentage of AIDS patients taking anti-HIV drugs and may lead to loss of therapeutic effectiveness. This proposal is to evaluate and develop one of five highly potent new antiviral phosphonates of our design for treatment of drug resistant HIV infection.